Diabetes promotes atherosclerosis in humans, greatly increasing the risk of developing cardiovascular disease. Compelling clinical data show that improving glycemic control early in life has long-term beneficial effects on cardiovascular events in human subjects with type 1 diabetes. Macrophages are likely to play a key role in the stimulatory effects of diabetes on atherosclerosis. Our preliminary studies demonstrate that in addition to stimulating a pro-inflammatory response, diabetes and elevated glucose levels lead to an increased expression of an enzyme that esterifies fatty acids (long-chain acyl-CoA synthetase 1;ACSL1) in macrophages, suggesting a close connection between the inflammatory capacity and ACSL1 in macrophages, diabetes and states of hyperglycemia. Strikingly, the stimulatory effects of diabetes on atherosclerotic lesion formation can be completely prevented by deleting ACSL1 in myeloid cells. No such effect is seen in non-diabetic mice, suggesting that the discovered mechanism is selective for diabetes. The protective effect of ACSL1-deficiency correlates with a reduced release of pro-inflammatory mediators from macrophages. The overall hypothesis of this project is that diabetes promotes atherosclerosis largely through increased glucose uptake in macrophages, which promotes an inflammatory macrophage phenotype that requires ACSL1. Our goal for the proposed project is to address two questions: 1). Does increased glucose uptake in macrophages enhance their pro-inflammatory capacity and atherosclerosis through a mechanism that requires ACSL1?;2). What is the ACSL1-dependent mechanism of glucose-mediated macrophage activation? PUBLIC HEALTH RELEVANCE: These studies will increase our understanding of the molecular and cellular mechanisms involved in diabetes- accelerated atherosclerosis and cardiovascular disease. Identification of such mechanisms might help develop treatment strategies to target cardiovascular complications, and other complications, associated with diabetes.